Exercise in patients with lymphedema: a systematic review of the contemporary literature

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1 J Cancer Surviv (2011) 5: DOI /s REVIEWS Exercise in patients with lymphedema: a systematic review of the contemporary literature Marilyn L. Kwan & Joy C. Cohn & Jane M. Armer & Bob R. Stewart & Janice N. Cormier Received: 26 August 2011 / Accepted: 28 September 2011 / Published online: 16 October 2011 # Springer Science+Business Media, LLC 2011 Abstract Background Controversy exists regarding the role of exercise in cancer patients with or at risk for lymphedema, particularly breast. We conducted a systematic review of the contemporary literature to distill the weight of the evidence and provide recommendations for exercise and lymphedema care in breast cancer survivors. Methods Publications were retrieved from 11 major medical indices for articles published from 2004 to 2010 using search terms for exercise and lymphedema; 1,303 potential articles were selected, of which 659 articles were reviewed by clinical lymphedema experts for inclusion, yielding 35 articles. After applying exclusion criteria, 19 articles were selected for final M. L. Kwan (*) Division of Research, Kaiser Permanente, 2000 Broadway, Oakland, CA 94612, USA Marilyn.L.Kwan@kp.org J. C. Cohn Penn Therapy and Fitness, Good Shepherd Penn Partners, Philadelphia, PA, USA joy.cohn@uphs.upenn.edu J. M. Armer Sinclair School of Nursing, University of Missouri, Columbia, MO, USA armer@missouri.edu B. R. Stewart College of Education, Sinclair School of Nursing, University of Missouri, Columbia, MO, USA StewartB@missouri.edu J. N. Cormier Department of Surgical Oncology, UT MD Anderson Cancer Center, Houston, TX, USA jcormier@mdanderson.org review. Information on study design/objectives, participants, outcomes, intervention, results, and study strengths and weaknesses was extracted. Study evidence was also rated according to the Oncology Nursing Society Putting Evidence Into Practice Weight-of-Evidence Classification. Results Seven studies were identified addressing resistance exercise, seven studies on aerobic and resistance exercise, and five studies on other exercise modalities. Studies concluded that slowly progressive exercise of varying modalities is not associated with the development or exacerbation of breast cancer-related lymphedema and can be safely pursued with proper supervision. Combined aerobic and resistance exercise appear safe, but confirmation requires larger and more rigorous studies. Conclusions Strong evidence is now available on the safety of resistance exercise without an increase in risk of lymphedema for breast cancer patients. Comparable studies are needed for other cancer patients at risk for lymphedema. Implications for cancer survivors With reasonable precautions, it is safe for breast cancer survivors to exercise throughout the trajectory of their cancer experience, including during treatment. Keywords Lymphedema. Breast cancer. Exercise. Physical activity. Systematic review. Literature review Introduction Lymphedema is a condition of the lymphatic system caused by a disruption of lymph transport. This perturbation leads to the accumulation of protein-rich fluid, resulting in swelling within the subcutaneous tissues of the affected body part [1, 2]. The condition may be acute or chronic, transient or progressive. If left untreated, it can become permanent and disfiguring. The effects of lymphedema on

2 J Cancer Surviv (2011) 5: an individual can lead to functional impairment, social and emotional distress, and poor quality of life [3 12]. Lymphedema can generally be classified into primary and secondary etiologies [13, 14]. Primary lymphedema is rare with no known acquired causes. It develops from an insufficiency in the structure and/or function of the lymphatic system that is characterized by malfunction of the lymphatic system in keeping up with the lymph load demands of the affected body part [14 16]. Secondary lymphedema, which is more commonly diagnosed in developed countries, is often caused by the disruption or compression of the lymphatic system resulting from tumors or their treatment. A recognized risk factor for secondary lymphedema is the surgical removal of axillary lymph nodes and/or radiation therapy to the axilla for breast cancer treatment, which can result in swelling of the arm, hand, or adjacent trunk quadrant [17]. Lymphedema can also occur in the head/neck region, trunk, and lower extremities following the treatment of head/neck, gynecologic, and genitourinary malignancies [14, 17, 18]. About 12 million cancer survivors currently reside in the USA [19], and at least 2.5 million are female breast cancer survivors [20]. The incidence of breast cancer-related lymphedema (BCRL) is estimated conservatively to be about 26% at 2 years after surgery [17]. Consequently, the risk-reduction and management of treatment sequelae, such as lymphedema, have grown in importance for breast cancer survivors and their clinicians. The importance of exercise in cancer prevention and control has emerged over the last 20 years [21 23]. For individuals with chronic conditions such as cancer, it is recommended that these individuals be as physically active as their abilities and conditions allow and to avoid inactivity [24]. Upper body exercise has historically been discouraged for breast cancer survivors following axillary lymph node dissection and/or radiation [25]. This unsubstantiated recommendation stemmed from the belief that upper body exercise might induce or exacerbate upper extremity lymphedema [26, 27]. Beginning with the 1998 seminal study of dragon boat racing in breast cancer survivors [28, 29], recent studies and reviews, including well-designed randomized controlled trials (RCT), have challenged this belief by demonstrating that there is no association between upper body exercise and the onset or worsening of BCRL [30 32]. Evidence is also emerging which establishes that exercise, including aquatic physical therapy [33] and weight lifting [34], may not exacerbate lower extremity lymphedema. Given the controversy regarding the role of exercise in patients with or at risk for lymphedema, we performed a systematic review of the peer-reviewed literature from 2004 to 2010 to distill the weight of the evidence and provide best practice recommendations for exercise and lymphedema care. Findings focus predominantly on BCRL as most of the published literature to date addresses lymphedema in breast cancer survivors. Methods This systematic review of literature on exercise and lymphedema management was jointly commissioned by the American Lymphedema Framework Project (ALFP) and the International Lymphoedema Framework (ILF) to update the ILF Best Practices document, which summarized the literature up until 2003[35]. A systematic review of the literature for articles related to exercise and lymphedema was performed in two phases (Fig. 1). For the first phase, a reference librarian searched 11 major medical indices (PubMed-MEDLINE, CINAHL, Cochrane Library databases (Systematic Reviews and Controlled Trials Register), PapersFirst, ProceedingsFirst, Worldcat, PEDro, National Guidelines Clearing House, ACP Journal Club, and Dare) for articles published from 2004 to 2010 using keywords related to lymphedema (lymphedema, lymphodema, lymphoedema, elephantiasis, swelling, edema, and oedema). Article archives of the authors and reference lists from related articles were also examined through A total of 5,927 articles were retrieved and 4,624 articles not relevant to lymphedema research were excluded by research associates (screen 1). The remaining 1,303 articles were reviewed by two editors for inclusion (lymphedema related, 10 cases) and exclusion (non-refereed articles) criteria, and a total of 644 articles were excluded, thus leaving 659 articles for the exercise review (screen 2). Translation was requested for non-english language articles directly from the relevant authors, and duplicate articles were removed. Articles with no English translation available were excluded. For the second phase, keywords for exercise were applied (exercise, physical activity, movement, physical therapy, physiotherapy, strength training, resistance training, and aerobic fitness). A total of 39 articles on exercise were selected and subsequently reviewed by the first and second authors (screen 3). Inclusion criteria for the final review included valid epidemiologic study design or literature review (randomized clinical trial, cohort study, case control study, meta-analysis, and systematic review); primary or secondary study outcome was lymphedema; and evident classification of exercise exposure into a priori domains of resistance exercise, aerobic and resistance exercise, and physical therapy. A total of 20 studies were excluded for the following reasons: case-series design (n=5), abstract only (n=3), exercise was outcome or lymphedema was covariate only (n=3), general exercise and cancer overview with no

3 322 J Cancer Surviv (2011) 5: the material. Information was abstracted on study design/ objectives, participants, outcomes, intervention, results, and study strengths and weaknesses. The two authors rated the totality of the evidence in the three exercise domains using the research grading system from the Oncology Nursing Society (ONS) Putting Evidence into Practice (PEP) classification (Table 1) [36]. The final PEP rating (recommended for practice, likely to be effective, benefits balanced with harms, effectiveness not established, effectiveness unlikely, and not recommended for practice) was agreed upon by consensus among all authors. This PEP rating system was chosen due to its high reliability and accessibility for evidence-based practice guidelines when compared with other published rating methods [37]. Summary of selected studies Resistance exercise studies (Table 2) Level of evidence: likely to be effective Fig. 1 Literature review process for exercise and lymphedema systematic review ( ) lymphedema information (n=2), aquatic therapy or dance (n=2), duplicate study (n=1), and other (n=4). Any disagreements were resolved by discussion in order to arrive at consensus. The remaining 19 studies met the inclusion criteria for this review (screen 4) and were categorized into the a priori domains of (1) resistance exercise only (n=7); (2) aerobic and resistance exercise combined (n=7); and (3) other exercise, primarily physical therapy (n=5). Each article was summarized by one author and reviewed by the other author to ensure appropriate and accurate representation of The physical activity and lymphedema (PAL) trial [38, 39] is the largest RCT to date with the longest follow-up to evaluate the impact of weight lifting on lymphedema outcomes in 141 breast cancer survivors previously diagnosed with BCRL [40]. One group of 71 women was randomly assigned to the twice-weekly weight-lifting program with no upper limit on weight progression while the other group of 70 women was assigned to the control group and asked not to change their exercise level during the study. All participants in the weight-lifting group were required to wear a compression garment for the arm and hand while weight lifting. The main outcome was change in arm and hand swelling at 1 year, as measured by an absolute increase of 5% or more by water displacement of the affected and unaffected limbs. Other outcomes included incident exacerbations of lymphedema, amount and severity of lymphedema symptoms, and muscle strength. Compared with the control group, weight lifting did not significantly affect the severity of BCRL, and the regimen decreased the number and severity of arm and hand symptoms, increased muscular strength, and reduced the incidence of lymphedema exacerbations as assessed by a lymphedema specialist. Adherence was high at 85%. Of note, the intervention was delivered in community fitness centers in anticipation of possibly disseminating the weightlifting program if found to be effective. A follow-up equivalence study from the PAL trial was published on the impact of the weight-lifting program compared to no exercise on BCRL risk in 154 randomized breast cancer survivors from 1 to 5 years post-breast cancer surgery (including lymph node removal) and no clinical

4 J Cancer Surviv (2011) 5: Table 1 Putting Evidence into Practice (PEP) Weight-of-Evidence Classification Schema Weight-of-evidence category Description Examples Recommended for practice Likely to be effective Benefits balanced with harms Effectiveness not established Effectiveness unlikely Not recommended for practice Effectiveness is demonstrated by strong evidence from rigorously designed studies, meta-analyses, or systematic reviews. Expected benefit exceeds expected harms Effectiveness has been demonstrated by supportive evidence from a single rigorously conducted controlled trial, consistent supportive evidence from well-designed controlled trials using small samples, or guidelines developed from evidence and supported by expert opinion. Clinicians and patients should weight the beneficial and harmful effects according to individual circumstances and priorities Data currently are insufficient or are of inadequate quality. Lack of effectiveness is less well established than those listed under not recommended for practice Ineffectiveness or harm is clearly demonstrated, or cost or burden exceeds potential benefits At least two multisite, well-conducted, randomized, controlled trials (RCTs) with at least 100 subjects Panel of expert recommendation derived from explicit literature search strategy; includes thorough analysis, quality rating, and synthesis of evidence One well-conducted RCT with fewer than 100 patients or at one or more study sites Guidelines developed by consensus or expert opinion without synthesis or quality rating RCTs, meta-analyses, or systematic reviews with documented adverse effects in certain populations Well-conducted case control study or poorly controlled RCT Conflicting evidence or statistically insignificant results Single RCT with at least 100 subjects that showed no benefit No benefit and unacceptable toxicities found in observational or experimental studies No benefit or excess costs or burden from at least two multisite, well-conducted RCTs with at least 100 subjects Discouraged by expert recommendation derived from explicit literature search strategy; includes thorough analysis, quality rating, and synthesis of evidence Based on information from Mitchell and Friese [36] signs of BCRL [41]. Similar to the previous study, incident BCRL was identified by an interlimb difference of 5% or more by water displacement at 1 year follow-up. Progressive weight lifting did not increase the incidence of BCRL: 11% (8/72) in the weight-lifting group and 17% (13/75) in the control group experienced incident BCRL onset (p equivalence=0.04) while among women with 5 lymph nodes removed, 7% (3/45) in the intervention group and 22% (11/49) in the control group had incident BCRL onset (p equivalence=0.003). Therefore, this study supports the safety of weight lifting in women with breast cancer and suggests that weight lifting will not increase BCRL risk. The Weight Training for Breast Cancer Survivors study is another RCT that examined the effects of weight training on the incidence and symptoms of lymphedema in 45 breast cancer survivors who were up to 36 months postadjuvant therapy and had axillary lymph node dissection [42]. Women in the intervention group (n=23) met twiceweekly for weight training sessions over 6 months while women in the control group (n=22) were told not to change their exercise level during the study. Women with BCRL were not required to wear a compression sleeve during exercise, unless specified by their clinician. Lymphedema onset was measured by a 2-cm difference in arm circumference of the affected and unaffected arms, along with self-report of symptoms and clinical diagnosis. No significant change in difference of arm circumferences (p= 0.40), nor self-reported incidence of BCRL (p=0.22), was found between the two groups. Adherence to the intervention was high (80%). Study limitations were BCRL being a secondary outcome and a few randomly selected cases having BCRL at baseline. A large RCT of 204 early stage breast cancer patients who had breast surgery including axillary node dissection evaluated the impact of an intervention of two rehabilitation programs, one of no activity restrictions in daily living combined with a moderate resistance exercise program and the other of activity restrictions combined with a usual care program [43]. The no activity restrictions group followed a supervised physical therapy program at an outpatient clinic that emphasized moderate progressive resistance exercise training two to three times per week. The activity

5 324 J Cancer Surviv (2011) 5: Table 2 Summary of lymphedema resistance exercise studies ( ); overall recommendation: likely to be effective Author (year) Study design/objectives Participants Outcomes Intervention Results Study strengths Study weaknesses Schmitz (2009) [38] Schmitz (2010) [41] Ahmed (2006) [42] RCT to examine the effect of twice-weekly progressive weight lifting RCT to examine the effect (safety) of twice-weekly progressive weight lifting RCT to examine the effects of weight training on the incidence and symptoms of LE 141 breast cancer survivors with stable LE 154 breast cancer survivors at risk for BCRL 45 breast cancer survivors (4 36 months status post-axillary node dissection) (1) Change in arm and hand swelling as measured by water displacement (2) Incidence of exacerbations of LE, number and severity of LE symptoms, muscle strength. (1) Change in arm and hand swelling as measured by water displacement (2) Clinician-defined BCRL based on the Common Toxicity Criteria version 3.0 criteria including interlimb differences, changes in tissue tone or texture, and symptoms (1) Swelling measured using arm circumference (baseline and 6 months) (2) Self-reported diagnosis and symptoms Studying group (n=71): twice-weekly (90 min) supervised weight lifting for 13 weeks followed by twice-weekly unsupervised exercise for 39 weeks Control group (n=70): no change in exercise level Study group (n=71): twiceweekly (90 min) supervised weight lifting for 13 weeks followed by twice-weekly unsupervised exercise for 39 weeks Control group (n=70): no change in exercise level Study group (n=23): twiceweekly exercise with fitness trainers for 6 months Control group (n=22): no exercise program 130 women completed follow-up at 1 year Proportion of women with 5% increase in swelling similar between groups Weight-lifting group had improvement in selfreported severity of LE symptoms, upper and lower body strength, and a lower incidence of LE exacerbations No serious adverse events reported 134 women completed follow-up at 1 year Proportion of women who had incident BCRL onset was 11% in the intervention group and 17% in the control group Among women who had 5 nodes removed, incident BCRL onset was 7% in intervention group and 22% in the control group Clinician-defined BCRL occurred in 1 woman in the intervention group and 3 women in the control group Over 6 months, group mean changes in circumference <2 cm At 6 months, 2/16 in study group and 1/16 in control group reported onset of LE At 6 months, 3/23 in control group and 0 in study group reported an increase in LE Largest study to date to examine weight lifting in breast cancer survivors with LE Evaluations for LE exacerbations not completed by a single therapist Long follow-up Some participants might have disclosed their randomization during Weight-lifting protocol with no upper limit on resistance level Intervention delivered in community centers Included diverse population 1 to 15 years posttreatment Largest study to date to examine weight lifting in breast cancer survivors Long follow-up Weight-lifting protocol with no upper limit on resistance level Intervention delivered in community centers Included diverse population 1 to 15 years posttreatment evaluations for perceived exacerbations Marginal significance of a treatment effect on lean mass 80% adherence LE measures were secondary outcomes Validated surveys used for LE diagnosis and symptoms No repeated measures during intervention Inadequate capture of transient changes in LE

6 J Cancer Surviv (2011) 5: Table 2 (continued) Author (year) Study design/objectives Participants Outcomes Intervention Results Study strengths Study weaknesses Sagen (2009) [43] Irdesel (2007) [45] Kilbreath (2006) [44] Sander (2008) [46] RCT to evaluate the development of arm LE RCT to test the effect of exercise and compression garments versus exercise alone RCT to examine the efficacy of resistance and stretching exercise Case crossover series to examine the effectiveness 204 women with early stage breast cancer status postaxillary node dissection 19 patients with BCRL 22 early breast cancer patients 4 to 5 weeks post-surgery 14 breast cancer survivors diagnosed (1) Difference in volume between the affected and control arms (baseline, 3, 6, and 24 months) (2) Visual analogue scales (VAS) used to record pain and the sensation of heaviness during physical activity (3) Questionnaire recorded upper-limb physical activity, which included intensity, duration, and frequency of activities (1) Limb volume calculated from circumferential measurements (before treatment and during 2nd week and 1st,, 3rd, and 6th month) Study group (n=104): no activity restrictions (NAR) with supervised moderate progressive resistance exercise training 2 3 times a week Control group (n=100): activity restriction (AR) with standard information to avoid heavy physical activities, usual care physical therapy program weekly for 6 months Study group (n=10): exercise program consisting of upper extremity range of motion exercises and light resistive exercises 3 /day and prescribed a compression garment (40 mmhg) (2) Shoulder range of motion Control group (n=9): same exercise program, no compression (3) Symptoms potentially related to LE such as pain and tender points (1) Arm circumference with measures 4 5 weeks after surgery and 8-weeks after intervention (2) Range of motion of shoulder and strength (3) QOL assessed using Euro QOL-QLQ-C30 (1) Arm volume calculated using arm measurements; Study group (n=14): daily exercises aimed at increasing shoulder range of motion and strength (supervised by a physiotherapist 1 /week) Control group (n=8): no exercise or additional care Study group 1 (n=5): exercises 2 /week and symptoms Changes in arm volume did not differ significantly: 3 months. LE increased from 5% in the NAR group and 7% in the AR 24 months. LE 13% in both groups VAS ratings for the affected limb during physical activity significantly higher at 3 and 6 months, but no difference at 24 months 2 participants developed adhesive capsulitis with immobilization and 1 patient supraspinatus tendinopathy For both groups, most measurements did not differ from baseline For study group, significant improvements in distal measurements (2nd week and 3rd and 6th month) For control group, proximal circumference measurements showed significant improvement in only the 1st month After 8 weeks, a greater proportion of women in the control group had an limb difference 2 cm, compared with study group (p=0.03) No significant differences for strength and range of motion scores For both groups, significant increase in the calculated 1 Long-term follow-up 52 dropouts at 24 months Adherence 83% in study group and 89% in control group Supervised programs Initial assessments performed before surgery Objective criteria for defining LE volume difference >200 ml Activity level documented in questionnaire Repeated measures and long-term follow-up Small study Exercise program not supervised Homogeneity of sample Small sample size Early introduction of exercise Weekly checks and reiteration of exercise protocol Multiple longitudinal measurements Lack of blinding Short-term follow-up only Small sample size

7 326 J Cancer Surviv (2011) 5: Table 2 (continued) Author (year) Study design/objectives Participants Outcomes Intervention Results Study strengths Study weaknesses RM for all of the 6 exercises observed 1 repetition maximum (RM) taken every 1 2 weeks for 15 weeks No changes in arm volume A-B-A design with each subject serving as own control Study group 2 (n=5): exercises 3 /week and 1RM (2) QOL assessed using the RAND 36-Item Health Survey 1.0 and Functional Assessment of Therapy- Breast (FACT-B) with stage I or II disease at least 6 months posttreatment with no LE history of upper extremity resistive exercise program (6 upper extremity resistive exercises using free weights) No a priori hypothesis to initiate Group 2 intervention Significant changes in 4 subscales of quality of life (3) Self-report of arm differences Lack of randomization and blinding restrictions group was told to avoid heavy or strenuous physical activities and participated in the usual care physical therapy program. Arm volume increased significantly over time in both groups in both the affected and unaffected arms (p<0.001). A study limitation was 25% loss-to-follow-up at 2 years. Two small RCTs with limited follow-up were conducted to assess the effects of light resistance exercises on BCRL risk [44] and BCRL treatment [45]. Kilbreath et al. recruited 22 breast cancer patients within 4 to 5 weeks post-surgery and randomized them into an exercise group (n=14) and control group (n=8) with no blinding [44]. The 8-week exercise program consisted of daily stretches with a Theraband targeted towards increasing shoulder range of motion and shoulder strength. Primary outcomes included difference in arm circumference and self-report of symptoms. Fewer women in the exercise group had interlimb differences of 2 cm and in general reported fewer arm and breast symptoms. Irdesel et al. recruited 19 breast cancer survivors diagnosed with BCRL and randomized them into an exercise group (n=9) and exercise with compression garment group (n=10) [45]. The non-supervised 6-month exercise program consisted of upper extremity range of motion exercises and light resistive exercises three times a day, with ten repetitions each time. The second group participated in the same exercise program and was also prescribed a compression garment. Primary outcomes were difference in arm circumference, shoulder range of motion, and self-report of symptoms measured at multiple time points over 6 months. Almost all measures were improved in the group who exercised with a compression garment compared with the group who did not wear a garment. A small study of 14 breast cancer survivors diagnosed with early stage breast cancer who had no history of lymphedema tested the effectiveness of an exercise program consisting of upper extremity resistive exercises using free weights [46]. Two exercise regimens which differed by frequency of exercise (twice vs. three times weekly) were tested in the same group of women. Outcomes were arm volume calculated from arm measurements of both arms and quality of life as measured by validated survey instruments. No significant changes in arm volume were observed, and quality of life measures improved. Study limitations were its small sample size and each case serving as her control. Aerobic and resistance exercise studies (Table 3) Level of evidence: benefits balanced with harms The Supervised Trial of Aerobic Versus Resistance Training was a multicenter RCT in Canada of 242 breast cancer patients initiating adjuvant chemotherapy randomly

8 J Cancer Surviv (2011) 5: Table 3 Summary of lymphedema resistance and aerobic exercise studies ( ); overall recommendation: benefits balanced with harms Author (year) Study design and objectives Participants Outcomes Intervention Results Study strengths Study weaknesses Courneya (2007) [47] Bicego (2006) [48] Cheema (2008) [25] De Backer (2009) [49] Prospective, 3-armed, RCT to examine the effects of aerobic and resistance exercise Literature review to assess the effects of aerobic exercise and upper extremity resistance training for women with or at risk for BCRL Systematic review of clinical studies that prescribed progressive resistance training (PRT) Systematic review of the effects of resistance training programs 242 breast cancer patients receiving adjuvant chemotherapy 6 studies of 177 women (14 w/either preexisting LE or LE developed during the study) and 2 studies of 45 women with pre-existing LE 10 clinical trials (4 uncontrolled trials, 1 controlled, and 5 RCTs) 538 breast cancer patients 24 studies (10 RCTs, 4 controlled clinical trials, and 10 uncontrolled trials) of 586 (54%) breast cancer, 196 (13%) prostate cancer, and 428 (25%) with others (1) QOL and fatigue assessed by FACT- Anemia scale (2) Fatigue, psychosocial functioning, physical fitness, and body composition (3) Chemotherapy completion rate (4) LE assessed using water displacement, measures taken at baseline (1 to 2 weeks after starting chemotherapy), middle of chemotherapy, 3 4 weeks and 6 months after chemotherapy Evaluation of study design (2 RCTs), Sackett level of evidence (5 low evidence), and methodological quality (1) Physiological, functional, and psychological outcomes (2) Study quality assessed using the Delphi for RCTs, non- RCTs, and uncontrolled trials Evaluation of study design and methodological quality using 10 defined criteria Study group 1 (n=78): aerobic exercise training (AET) 3 /week on cycle ergometer, treadmill, or elliptical beginning at 60% of their vo2max for weeks 1 6, progression to 70% weeks 7 12, and 80% beyond week 12; duration at 15 min progressing to 45 min at week 18 Study group 2 (n=82): resistance exercise training (RET) 3 /week 2 sets of 8 12 repetitions of 9 different exercises at 60 70% of 1 repetition maximum (RM); resistance increased by 10% after completing at least 12 repetitions Study group 3 (n=82): usual care (UC) not to start exercise program No difference between groups in QOL, fatigue, depression, or anxiety AET improved self-esteem (p=0.015), preserved aerobic fitness (p=0.006), and maintained body fat levels (p=0.076) RET improved self-esteem (p=0.018), muscular strength (p<0.001), lean body mass (p=0.015), and chemotherapy completion rate (p=0.033) Exercise did not result in LE or adverse events Not applicable Aerobic exercise and upper extremity resistance training neither initiated nor exacerbated LE More research required with large sample size, rigorous design, and better outcome measures of LE Multicenter recruitment LE assessed as secondary outcome Moderate sample size 70.2% adherence rate Validated assessment measures Low recruitment rate Repeated measures Study sample homogeneous First study to report strength gains during chemotherapy Focus on body composition change Review of the physiologic rationale for the effect of exercise and compression in at-risk limbs Suggestions on improved measurement techniques to assess change in lymphatic function Not applicable No exacerbation of LE Tabular summary of study quality, design, interventions, and outcomes Breast cancer patients after surgery can receive health-related benefits from PRT More research required with welldesigned RCTs with standardized reporting of interventions and adverse events Not applicable Most studies included combination of resistance and aerobic training 3 studies focused on LE in breast cancer patients - none found an increase in LE after training Tabular summary display of study quality, design, interventions, and outcomes Tabulated exercise intensity Cardiopulmonary and muscle Reviewed studies in patients with respect to race and education No tabular summary of study quality, design, interventions, and outcomes None None

9 328 J Cancer Surviv (2011) 5: Table 3 (continued) Author (year) Study design and objectives Poage (2008) [50] Literature review of the effective interventions for the treatment of secondary LE Hayes (2009) [51] RCT, single-blind trial to evaluate the effect of a supervised, mixed-type exercise program Portela (2008) [52] 3-arm RCT to explore the feasibility of exercise program Participants Outcomes Intervention Results Study strengths Study weaknesses 218 articles ( ) 32 women with LE after breast cancer 44 breast cancer survivors who had received breast surgical treatment within the past 5 years (only 34 completed the study) (1) Evidence-based review of clinical practice guidelines, systematic reviews, and re search studies (2) Studies categorized according to Oncology Nursing Society Weight of the Evidence classification system LE status assessed by bioimpedance spectroscopy and perometry measures taken at baseline, immediately postintervention, and at 12-week follow-up (1) Functional evaluation measured using the disabilities of the arm, Shoulder, and Hand (DASH) questionnaire (2) Shoulder range of motion examined through goniometry function improved with training, but no effects found for body composition, endocrine and immune function, and hematological variables Not applicable Interventions recommended: Study group (n=16): participated in 12-week mixed-type exercise program, including aerobic and resistance exercise; choice of whether or not to wear a compression garment during the exercise sessions Control group (n=16): taught to continue habitual activities Study group 1: Gym-exercise group and home-exercise group met with physical therapists for training in their assigned exercise program. Both groups performed 2 resistance training session and 3 aerobic training sessions per week for 26 weeks Study group 2: Gym-exercise group met with the staff once a week, whereas the home-exercise group complete decongestive therapy (CDT), compression bandaging, and infection treatment with antibiotics Interventions likely to be effective: maintain optimal body weight and manual lymph drainage (MLD) Interventions of benefits balanced with harms: exercise, prophylactic antibiotics for recurrent infections, and surgery Interventions of effectiveness is not established: compression garments, hyperbaric oxygen, low-level laser therapy, nanocrystalline silver dressing on lymphatic ulcers, pneumatic compression pump, and simple lymphatic drainage Interventions not recommended for practice: drug therapy (diuretics and benzopyrenes) No changes in mean volume measures over time observed for either group 2 women in the study group no longer had evidence of LE Decrease in self-reported disability in gym and home groups, but not in control Increase in flexion range of motion in gym, but not in home or control groups with various malignancies Systematic literature review with a clinical focus Developed evidence tables Repeated measures with the same assessor who was blinded to study group 1 physical therapist blinded to group assignment 2 intervention groups (gym exercise and home exercise) None Small sample size 70% adherence Response bias most likely present with more active, educated, affluent women in study 38% lacked measurable LE at baseline No assessment of compression use during exercise Small sample size 10 participants did not complete the study

10 J Cancer Surviv (2011) 5: Table 3 (continued) Participants Outcomes Intervention Results Study strengths Study weaknesses Author (year) Study design and objectives met with the staff once a week for the first 3 weeks and then met once a month Low adherence rate (47% for aerobic exercise and 63% for strengthening exercise in the gym-exercise group; 71% for aerobic exercise and 86% for strengthening exercise in the home-exercise group) No differences in shoulder abduction in any group Control group: received usual care provided by their physicians (3) Exercise tolerance assessed by a 12-min walk test Increase in external rotation in gym and home groups but not in control (4) Handgrip strength examined using a handheld dynamometer Increase in the 12-minute walk test only in home group but not in gym and control group (5) QOL Spanish version FACT-B No significant effects in BMI, handgrip strength, and QOL among 3 groups (6) Development of LE volumetric edema gauge For the endurance training, all achieved the 30-minute duration at the set intensity Adverse effects in exercise programs included high blood pressure, severe headache, hypoglycemia assigned to usual care (n=82), supervised resistance exercise (n=82), or supervised aerobic exercise (n=78) for the duration of their chemotherapy (median=17 weeks) [47]. Lymphedema was a secondary outcome and measured by water displacement while the primary outcomes were cancer-specific quality of life and fatigue. Neither the resistance exercise training nor the aerobic exercise training triggered the onset of lymphedema. One study limitation was a low adherence rate of 70.2%. Four literature reviews have been conducted on the safety of aerobic and/or upper resistance exercise in breast cancer survivors, with a secondary focus on BCRL [25, 48 50]. Two of these reviews focused primarily on resistance exercise, yet in the context of the review, the authors evaluated trials that examined a combination regimen of resistance and aerobic exercise [25, 49]. All reviews concluded that breast cancer patients can derive healthrelated and clinical benefits from various exercise programs and that exercise neither initiated nor exacerbated BCRL symptoms [48, 50]. Methodological limitations in study design and sample size were acknowledged. The reviews also called for more robustly designed RCTs of targeted exercise regimens with long-term follow-up during breast cancer treatment to rigorously test the effects of aerobic exercise and upper resistance exercise in breast cancer survivors. A small pilot RCT of 32 breast cancer survivors with lymphedema were randomized into an exercise intervention group (n=16) and control group of usual care (n=16) [51]. The exercise program was 20 group sessions of a supervised, 12-week mixed-type exercise program, including aerobic and resistance exercise, and use of a compression sleeve was left up to the participant s discretion. Lymphedema was assessed by bioimpedance spectroscopy (impedance ratio between limbs) and perometry (volume differences between limbs) at baseline, immediately after each exercise session, and at 12-week follow-up. No change in mean ratio and volume measures were observed over time. Study limitations were 38% of the participants lacking measurable evidence of BCRL at baseline and a low adherence rate of 70%. Another small pilot RCT tested the feasibility of implementing a mixed aerobic and resistance exercise intervention by assigning 44 women previously diagnosed with breast cancer who had surgery to one of three groups: gym exercise, home exercise, and non-exercise [52]. Both exercise groups were initially trained by physical therapists and then participated in two resistance training sessions and three aerobic training sessions per week for 26 weeks. A volumetric edema gauge was used to monitor the onset of BCRL. Overall, the side effects were minimal in both exercise groups after participating in the study, although study limitations included a high proportion of dropouts

11 330 J Cancer Surviv (2011) 5: (n=10) and low adherence rates of 47% for aerobic exercise and 63% for strengthening exercise in the gymexercise group, and 71% for aerobic exercise and 86% for strengthening exercise in the home-exercise group. Other exercise studies (Table 4) Level of evidence: effectiveness not established A pilot RCT was conducted on the effectiveness of a homebased exercise rehabilitation program to regain shoulder mobility after mastectomy and axillary node dissection in 27 breast cancer patients [53]. A total of 16 patients were assigned to the rehabilitation group and 11 were assigned to the usual care group. The rehabilitation group followed an 11-day (two sets per day, min per set) home-based rehabilitation program consisting of shoulder flexibility and stretching exercises that were described on videotape. The control and rehabilitation groups both received the usual standard information given to post-operative patients, including information about diet, skin care, and a brochure called Exercise Guide after Breast Surgery. Forearm circumferences on both arms were measured before surgery and at 3 and 14 days post-surgery to assess for lymphedema. The home-exercise rehabilitation group had a significant increase in shoulder flexion range of motion compared with the usual care group (p=0.036), and while there was a significant decrease in forearm circumferences over time in both groups (p<0.001), no difference between the groups was detected. Several studies have examined the role of physiotherapy, such as standard arm exercises and deep breathing [54], on the post-surgical recovery after breast cancer surgery [55 57]. Beurskens et al. indicated that the RCT objective was to test the efficacy of a physical therapy treatment on shoulder function, pain, and quality of life in 30 breast cancer patients, yet the details of the treatment regimen were not specified [55]. de Rezende et al. conducted a RCT of directed- or free-physical therapy exercises on shoulder function and lymphatic disturbance in 60 post-operative breast cancer patients but had a short follow-up period of 42 days [56]. Methodological issues such as small sample size, lack of uniform intervention and intervention supervision, short follow-up, and lymphedema assessed as a secondary outcome were apparent in all studies. While study results generally support the role of physical therapy reducing pain, improving shoulder function, benefiting quality of life, and not exacerbating arm swelling, larger, well-designed RCTs with supervision of the intervention to ensure compliance are still needed. More recently, a 2010 RCT study of a physical therapy program consisting of manual lymph drainage, massage of scar tissue, and progressive active and active-assisted shoulder exercises found that women in the physical therapy group were less likely to develop BCRL compared to women in a comparison group which included only an educational strategy [57]. Yet, since the intervention was a mixed regimen, it is unclear if the shoulder exercises were directly associated with the reduction in BCRL risk. Discussion In the past 20 years, research efforts have grown to elucidate the benefits of exercise for cancer survivors. This growth has paralleled the gains made in overall cancer survivorship. Yet even today, many patients continue to believe that it is not safe to exercise due to the risk of lymphedema or other surgical or treatment-related complications. In the current systematic review, we found that the majority of exercise studies continue to address lymphedema risk in the breast cancer population. All studies concluded that there is no adverse effect from safe, slowly progressive exercise of varying modalities on the development or exacerbation of BCRL. However, risk of developing BCRL does persist and is reported to range from 13% at 2 years [43]; 17% at months [42]; 30% at 18 months [51]; and 17% at 2 6 years post-diagnosis [41]. Aside from studies in breast cancer patients, the literature is very limited with respect to exercise interventions in other patient populations with or at risk for lymphedema. Benefits of exercise after cancer diagnosis Numerous benefits of exercise on cancer survivorship have been reported. The 2010 American College of Sports Medicine (ACSM) Exercise Guidelines for Cancer Survivors state that some of the psychological and physiological challenges faced by cancer survivors can be prevented, attenuated, treated or rehabilitated through exercise [30]. These benefits include improved flexibility, reduced fatigue, increased strength, improved body image and quality of life, improved body composition, and decreased anxiety. Furthermore, the ACSM guidelines cite that exercise may be associated with a reduced risk of developing a recurrence or secondary cancer. Two additional literature reviews on exercise during cancer treatment also concluded that exercise offers physiologic and psychological benefits [31, 32]. Therefore, with reasonable precautions, it is safe for individuals to exercise throughout the trajectory of their cancer experience, including during treatment. The benefits to be gained by exercise far outweigh the minimal adverse effects reported. Exercise for a patient who is at risk for lymphedema or has been previously diagnosed with lymphedema has been

12 J Cancer Surviv (2011) 5: Table 4 Summary of other lymphedema exercise studies ( ); overall recommendation: effectiveness not established Author (year) Study design/objectives Participants Outcomes Intervention Results Study strengths Study weaknesses Torres Lacomba (2010) [57] Kilgour (2008) [53] Beurskens (2007) [55] RCT to examine the effectiveness of early physiotherapy RCT to examine the effectiveness of a self-administered, homebased exercise (HBE) rehabilitation program RCT to examine the efficacy of physiotherapy on shoulder function, pain and QOL 120 breast cancer patients after axillary lymph node dissection 27 breast cancer patients after axillary node dissection 30 breast cancer patients after axillary lymph node dissection >2 cm increase in arm circumference compared to nonaffected arm (1) Shoulder range of motion, strength, and grip strength (2) Forearm circumferences on both arms measured before surgery and at 3 and 14 days post-surgery (3) Diaries to monitor medication use, pain ratings, and ratings of perceived exertion during intervention period. (1) Pain in shoulder/arm using visual analogue scale (2) Shoulder mobility using a digital inclinometer (3) Shoulder disabilities during daily activities (Disabilities of the Arm, Shoulder and Hand [DASH] questionnaire) Study group (n=60): treated by a physiotherapist with a program of manual lymph drainage, massage of scar tissue, and shoulder exercises; educational instruction about risk and prevention of lymphedema Control group (n=60): received educational instructional only Study group (n=16): followed an 11-day HBE rehabilitation program of shoulder flexibility, stretching exercises described on videotape, 2 sets/day at min/set Control group (n=11): usual and standard information, including information about diet, skin care, and a brochure Exercise Guide after Breast Surgery Study group (n=15): physiotherapy (advice and arm and shoulder exercises) 2 weeks after surgery, 1 2 /weekly for the first 3 weeks, and 1 /week total number of treatments, 9. Home exercises for 10 min/day for 3 months Control group (n=15): leaflet containing advice and exercises for the first week after surgery 116 women completed 1 year follow-up Secondary lymphedema was more likely to be diagnosed in the control group compared with the study group (HR=0.26; 95% CI, 0.09, 0.79) Study group showed greater increase in shoulder flexion range of motion (p=0.003) and abduction range of 2motion (p=0.036) No significant differences in shoulder strength Increases in external rotation (p=0.036) and grip strength (p=0.001) in both groups Significant decrease in forearm circumferences over time (p<0.001) in both groups After 3 and 6 months, study group showed improvement in shoulder mobility and had less pain No change in handgrip strength and arm volume between the groups 10 patients study group reported improvement in participation in social activities and less avoidance of heavy household work (4) LE water displacement Improvement of shoulder mobility and shoulder/arm disabilities in the study group (5) Grip strength -hand-held dynamometer (6) QOL sickness impact profile-short questionnaire Treatment allocation was blinded Randomized groups of moderate size Long follow-up All assessments conducted by a single certified athletic therapist Presurgical assessment o f limb circumference Researcher blinded to treatment allocation Assessment of arm circumference change not completed by single physiotherapist Only 1 measure of BCRL prone to measurement error Small sample size No long-term follow-up 50% of women did not complete the exercise video intervention Small sample Homogeneity of sample LE a secondary outcome Patients in study group had physiotherapy done in a private practice of their choice (n=15), no observations of compliance Duration of exercise treatment varied from 1 to 3 months Only general details of physiotherapy intervention provided

13 332 J Cancer Surviv (2011) 5: Table 4 (continued) Author (year) Study design/objectives Participants Outcomes Intervention Results Study strengths Study weaknesses de Rezende (2006) [56] Moseley (2005) [54] RCT to compare 2 physiotherapy schemes, directed or free, on shoulder function and lymphatic disturbance Case series with a comparison group to examine changes in LE 60 breast cancer patients after axillary node dissection 38 women with unilateral secondary LE related to breast cancer treatment Comparison group was 28 women who received no intervention Shoulder movements measured with a universal full-circle manual goniometer Daily wound fluid production noted before and after the drains removed Measurements of arm circumferences performed with a universal tape measure (1) Arm volume measured by bioimpedance and perometry (2) Tissue resistance measured by tonometry (3) McGill QOL Questionnaire (4) Self-report of pain, heaviness, tightness, pins, and needles, cramping, burning sensations, and perceived arm size Study group 1 (n=30): directed group performed physiotherapy with a regimen of 19 exercises Study group 2 (n=30): free group performed exercises following the biomechanical physiological movements of the shoulder 3 exercises day #1 after surgery in both groups. At 48 h after surgery, exercises performed in 40-min sessions, 3 /week for 42 days Study group (n=38): 5 exercises combined with deep breathing followed by 1-min rest, 5 5 cycles of exercise and breathing over the 10-min period (25 exercises in total) After 1 week, 24 women continued the 10-min exercise regime morning and evening for 1 month Control group (n=28): no intervention and had previously been monitored for 1 month Directed group 1 with better flexion, adduction, and external rotational movements of the shoulder No significant difference in lymphatic disturbance between 2 groups Incidence of seromas not significantly different between the 2 groups After 10 min exercise, median reduction in arm volume of 52 ml. (p=0.004). Reduction sustained at 30 min (p=0.006), but fluid gradually returned, and by 60 min, the median volume returned to baseline. At 1 month, volume reduced 9% Truncal fluid not reduced significantly at any time point Tonometry reading did not change, except at 1 month for the anterior thorax (p=0.018) Arm heaviness and tightness decreased after exercise regime (p=0.05, 0.02, respectively), with reduction in tightness being sustained at 24 h (p=0.00) and reduction in heaviness at 24 h, 1 week, and 1 month Sensations of pins and needles reduced at 24 h and 1 week (p=0.030) Details of physiotherapy i nterventions provided Very early exercise intervention (24 h post-op) 90% compliance rate in the group who performed the regime over 1-month period Small sample size No information on blinding Lack of long-term follow-up Few limb measurements size changes closer to the elbow could have been missed Small sample size 37% dropouts (n=14) Lack of blinding Limited follow-up of 1 month